Throughout this application various publications are referred to in superscripts. Full citations for these references may be found at the end of the specification before the claims. The disclosures of these publications are hereby incorporated by reference in their entireties into the subject application to more fully describe the art to which the subject application pertains.
H. pylori is a gram-negative bacterium and lives microaerophilically in the gastric mucosa of its human host. It is related to 85 percent of gastric and 95 percent of duodenal ulcers1. Drug resistance is prevalent in clinical isolates of H. pylori. After less than thirty years of specific antibiotic treatment, it is increasingly difficult to eradicate H. pylori using a combination of two antibiotics with two weeks therapy2. Antibiotics with new targets and mechanisms of action are needed to treat H. pylori infections.
Gram negative bacteria are dependent on menaquinone as electron transporters in respiration and have maintained biosynthetic pathways for these essential metabolites3. In contrast, humans lack the pathway of menaquinone synthesis, and targeting the menaquinone pathway provides an anti-bacterial drug design approach. Recently, a menaquinone synthetic pathway has been proposed in Campylobacter and Helicobacter that differs from most bacteria4,5. In this pathway, 6-amino-6-deoxyfutalosine is synthesized by MqnA and cleaved at the N-ribosidic bond by a MTAN with specificity also extending to 5′-methylthioadenosine and adenosylhomocysteine as well as 6-amino-6-deoxyfutalosine. HpMTAN converts 6-amino-6-deoxyfutalosine to adenine and dehypoxanthine futalosine, the latter being used as the processor of menaquinone synthesis. The early reactions of this pathway do not exist in the normal bacterial flora of humans, making enzymes catalyzing these reactions appealing drug targets. HpMTAN is closely related to the 5′-methylthioadenosine/S-adenosylhomocysteine hydrolases (MTANs) found in other bacteria. The well-characterized MTANs are associated with quorum sensing and S-adenosylmethionine recycling in most species and are not essential for bacterial growth6. Transition state analogue inhibitors of picomolar to femtomolar affinity have been developed to interrupt bacterial functions associated with quorum sensing6,7.
The present invention addresses the need for new compounds that selectively block the growth of H. pylori. 